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Researchers identify major driver of inflammatory bowel and related diseases

Researchers have discovered a major driver of inflammatory bowel disease (IBD) and several other immune disorders that affect the spine, liver and arteries, raising hopes for millions of people worldwide.

The breakthrough is particularly exciting because the newly found biological pathway can be targeted by drugs that are already used, with work under way to adapt them to patients with IBD and other conditions.

“What we have found is one of the very central pathways that goes wrong when people get inflammatory bowel disease and this has been something of a holy grail,” said Dr James Lee, the group leader of the genetic mechanisms of disease laboratory at the Francis Crick Institute in London.

Lee added: “Even for pure, fundamental immunology this is a really exciting discovery. But to show this is dysregulated in people who get disease not only gives us a better understanding of the disease, it tells us this is something we can treat.”

More than half a million people in the UK have inflammatory bowel disease, the two main forms of which are Crohn’s disease and ulcerative colitis, with at least 7 million affected globally. They arise when the immune system attacks the bowel, causing an array of debilitating symptoms from abdominal pain and weight loss to diarrhoea and blood in stools. While medicines such as steroids can ease the symptoms, some patients require surgery to remove part of their bowel.

Lee’s research team “stumbled” on the discovery after investigating a “gene desert”, a stretch of DNA on chromosome 21 that does not code for proteins, which has previously been linked to IBD and other autoimmune diseases. Writing in Nature, they describe how they found a section of DNA that behaves like a volume control for nearby genes. This “enhancer” was seen only in immune cells called macrophages where it boosted a gene called ETS2 and ramped up the risk of IBD.

Through gene editing experiments, the scientists showed that ETS2 is central to the inflammatory behaviour of macrophages and their ability to damage the bowel in IBD. “There’s been a search for some time for the central drivers of this pathogenic process, and this is what we’ve stumbled on,” said Lee, who is also a consultant gastroenterologist at the Royal Free hospital and UCL.

The same biological pathway is thought to drive other autoimmune disorders, including ankylosing spondylitis, which causes spine and joint inflammation in about one in 1,000 people worldwide, and rarer autoimmune diseases that affect the liver and arteries.

While there are no drugs that specifically target the ETS2 gene, the scientists identified a class of anticancer drugs called MEK inhibitors that they suspected would dampen the gene’s activity. In laboratory tests, the drugs performed as expected, reducing inflammation in gut samples from patients with IBD.

Because MEK inhibitors have side-effects in other organs, the scientists have begun work to adapt the medicine so it targets only a patient’s macrophages. This is done by creating a “conjugate” where the drug molecule is attached to a synthetic antibody that binds only to the target cells. “It’s safer because it’s more targeted and you can use a lower dose,” said Lee. “We have already developed the antibody conjugate, I have it sitting in my freezer.”

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Clinical trials are still needed to see whether the adapted drug reduces IBD and other autoimmune conditions, but because MEK inhibitors are already used in cancer patients, researchers hope that process could be swift and potentially completed within five years.

In further work, the scientists found that the ETS2 gene is at least half a million years old and was carried by neanderthals and other archaic humans. “It has been preserved over evolutionary history probably because it is important in early bacterial responses,” said Lee. “So you wouldn’t want to knock it out all together. You just need to turn down its activity by 50% and the effect of that may be enough.”

Ruth Wakeman at Crohn’s and Colitis UK said: “Crohn’s and colitis are complex, lifelong conditions for which there is no cure, but research like this is helping us to answer some of the big questions about what causes them. This research is a really exciting step towards the possibility of a world free from Crohn’s and colitis.”

source: https://www.theguardian.com/society/article/2024/jun/05/bowel-disease-hope-researchers-find-biological-pathway